Phosphorylation regulates E3 ligase activity of Mdm2

The Mdm2 oncogene is associated with the negative regulation of the tumor suppressor p53 in an autoregulatory feedback loop in response to DNA damage. It has been assumed that Mdm2 functions in this pathway as an E3 ubiquitin ligase and is Mdm2's principal function under all conditions. However, the E3 ligase activity can function either as ubiquitin or nedd8 E3 ligase. This activity is dependent on specific tyrosine kinases that are activated in response to DNA damage signaling or growth factor signaling pathways. The E3 ligase activity can have a distinct effect on the substrate by either stabilizing or signaling destruction. In the context of growth signaling pathways, we show that Src phosphorylation of Mdm2 recruits Ubc12 (nedd8 E2 enzyme). This results in the neddylation of the tumor suppressors pVHL and p53. The neddylation of pVHL prevents the association with p53, thereby attenuating the induction of anti-angiogenic genes. The phosphorylation of Mdm2 by Src is in the Zinc domain, and we found that this domain is a key regulatory domain for the recruitment of E2 enzymes. These findings suggest that the role of Mdm2 is more complex than just functioning as an E3 ubiquitin ligase to signal for the destruction of p53. © FASEB.